Journal of Neuroscience最新文献

Dopamine (DA) is critically involved in processes such as reward anticipation, attention, and decision-making. The present study examined the temporal dynamics of phasic DA transients in the nucleus accumbens core (NAcC) during a visual decisional task based on signal detection theory, using the fluorescent DA sensor dLight1.3b. During the decision-making phase, DA transients in the NAcC encoded real-time outcome expectancy, apparently reflecting the confidence of male rats in their choices. Reward prediction errors (RPEs) emerged following reward delivery and omission and were amplified under conditions of increased uncertainty, produced either by degrading the visual target or introducing interfering distraction. Moreover, DA transients were elicited on both visual signal and no-signal trials. These findings demonstrate that DA fluctuations in the NAcC reflect the RPE that incorporates confidence and levels of uncertainty, emphasizing an involvement of nucleus accumbens DA in adaptive decision-making.Significance Statement This study reveals a novel involvement of the widely studied neurotransmitter dopamine in coding the confidence of choice responses in well-established visual decision-making in the rat. Reward prediction errors were shown to emerge during manipulations of uncertainty, such as distraction. Similar phasic dopamine responses in the nucleus accumbens core occurred to both the occurrence and non-occurrence of the discriminative visual stimulus, showing for the first time that such dopaminergic responses are generated to interoceptive as well as exteroceptive discriminative stimuli. These observations thus enhance our understanding of the role of mesoaccumbens dopamine in perceptual decision-making.

Our ability to retrieve the names of objects in our environment is a fundamental aspect of everyday life. This process requires a complex, dynamic network of cortical and subcortical interactions. While the cortical constituents of this network have been extensively studied with intracranial recordings, the subcortical nodes of the naming network are unclear. We probed the role of the left medial pulvinar nucleus in naming with direct intracranial recordings and stimulation in eight humans (three male, five female) as they named objects using pictures and auditory and written descriptions. We found a spectrotemporal signature of naming in the left medial pulvinar nucleus, characterized by a low frequency (8-20 Hz) suppression, consistent across sensory modalities during naming, and absent during other non-naming language tasks. Within this frequency band, Granger causal interactions showed that the pulvinar nucleus received strong inputs from early visual, ventral temporal, and parahippocampal cortices. Direct thalamic stimulation reliably induced anomia, confirming that the left medial pulvinar nucleus is a critical node in the distributed naming network.

The rate of cognitive decline in Alzheimer's disease (AD) varies considerably from person to person. Numerous epidemiological studies point to the protective effects of cognitive, social, and physical enrichment as potential mediators of cognitive decline in AD; however, there is much debate as to the mechanism underlying these protective effects. The retrosplenial cortex (RSC) is one of the earliest brain regions with impaired functions during AD pathogenesis, and its activity is affected by cognitive, social, and physical stimulation, making it a particularly interesting region to investigate the influences of an enriched lifestyle on AD pathogenesis. In the current study, we use the 5xFAD mouse mode of AD to examine the impact of enriched housing conditions on cognitive function in AD and the viability of a particularly vulnerable cell population within the RSC-parvalbumin interneurons (PV-INs). Enriched housing conditions improved cognitive performance in female 5xFAD mice. These changes in cognitive performance coincided with restored functional connectivity of the RSC and preserved PV-IN density within this region. Along with preserved PV-IN density, there was an increase in the density of Wisteria floribunda agglutinin-positive perineuronal nets (WFA⁺ PNNs) across the RSC of 5xFAD mice housed in enriched conditions. Direct manipulation of WFA⁺ PNNs revealed that these extracellular matrix structures protect PV-INs from amyloid toxicity and may be the mechanisms underlying the protective effects of enrichment. Together, these results provide support for the WFA⁺ PNN-mediated maintenance of PV-INs in the RSC as a potential mechanism mediating the protective effects of enrichment against cognitive decline in AD.

Learning systems must constantly decide whether to create new representations or update existing ones. For example, a child learning that a bat is a mammal and not a bird would be best served by creating a new representation, whereas updating may be best when encountering a second similar bat. Characterizing the neural dynamics that underlie these complementary memory operations requires identifying the exact moments when each operation occurs. We address this challenge by interrogating human fMRI brain activation (13 females and 12 males) with a computational learning model that predicts trial-by-trial when memories are created versus updated. We found distinct neural engagement in anterior hippocampus and ventral striatum for model-predicted memory create and update events during early learning. Notably, the degree of this effect in hippocampus, but not ventral striatum, significantly related to learning outcome. Hippocampus additionally showed distinct patterns of functional coactivation with ventromedial prefrontal cortex and angular gyrus during memory creation and premotor cortex during memory updating. These findings suggest that complementary memory functions, as formalized in computational learning models, underlie the rapid formation of novel conceptual knowledge, with the hippocampus and its interactions with frontoparietal circuits playing a crucial role in successful learning.Significance statement How do we reconcile new experiences with existing knowledge? Prominent theories suggest that novel information is either captured by creating new memories or leveraged to update existing memories, yet empirical support of how these distinct memory operations unfold during learning is limited. Here, we combine computational modeling of human learning behaviour with functional neuroimaging to identify moments of memory formation and updating and characterize their neural signatures. We find that both hippocampus and ventral striatum are distinctly engaged when memories are created versus updated; however, it is only hippocampus activation that is associated with learning outcomes. Our findings motivate a key theoretical refinement that positions hippocampus is a key player in building organized memories from the earliest moments of learning.

Fast-spiking, nonadaptive inhibitory neurons in the thalamic reticular nucleus (TRN) critically gate the reciprocal communication between the thalamus and the cortex. Parvalbumin (PV) neurons express high levels of PV, the sole role of which appears to be calcium buffering. The significance of the PV protein-and its related high calcium-buffering capacity-under pathological conditions, especially in various neuropsychiatric disorders, is underappreciated. Deficiency of SHANK3, an important neuronal protein containing ankyrin, SH3, and PDZ, three canonical domains for protein recognition, causes behavioral changes relevant to autism spectrum disorders (ASDs). Here we report TRN PV neurons of Shank3-/- (exon 4-22 deletion) mice of either sex exhibit pronounced increases in burst firing occurrence, decreased tonic firing frequency, and faster dendritic calcium transient decay. We pinpointed reduced PV expression as the culprit and used the added buffer approach to confirm the decrease in calcium-buffering capacity in mutant neurons. Conversely, supplementing Shank3-/- PV neurons with extra EGTA reverses the abnormal action potential (AP) firing. In addition, the PV neurons from HCN2-/- mice exhibit consistent changes in neuronal excitability, PV expression, and calcium signaling. Together with the study of dopaminergic (DA) neurons in the ventral tegmental area (VTA), these results uncover reduced PV expression, calcium-buffering capacity, and altered neuronal excitability in Shank3-/- and HCN2-/- mice. This pathway, downstream of Shank3 deficiency and HCN channelopathy, may form an important pathological basis not only for ASD but also other neuropsychiatric disorders.